Flow cell, method for separating carrier-free radionuclides, and the radiochemical reaction thereof

ABSTRACT

The invention relates to a flow cell, a method for separating carrier-free radionuclides from a liquid or liquefiable target material, and the radiochemical reaction thereof. According to prior art, flow cells are known which require reaction volumes corresponding to the volume of the target material in order to carry out the desired reactions. The inventive flow cell (I) and method enable the reaction volume and thus the quantity of starting material, to be reduced by a multiple by reducing the cylinder volume (=reaction volume). As the radioactively marked product is present in very small quantities (picomole to nanomole), the HPL-chromatographic separation of the non-reacted starting material is significantly improved. The economic efficiency of the method is increased due to the fact that small quantities of starting material can be used.

The invention relates to a flow cell as well as to a method of separating carrier-free radionuclides from liquids or liquefiable target material and their radiochemical reactions.

Radionuclides can be made by nuclear conversion processes in a cyclotron, for example by irradiating a suitable target with protons. An exact description of a method of separating carrier-free radionuclides from a target liquid is known, for example, from German patent document DE 195 00 428.

From German patent document DE 195 00 428 a device is also known (a flow cell) for the separation of carrier-free radionuclides from a target liquid, which is comprised substantially of a cylinder of a glassy carbon (Sigradur®) and an axial platinum canula through which a cylindrical vessel can be filled or emptied through which the inert gas can be fed into the chamber. The system is fixed by means of a plastic mounting and is sealed. Into the lower end a flat funnel is worked which opens into the duct carrying off the water. In the head of the mounting, there is a gas feed line as well as an opening through which the gas can be discharge. The cylinder of glassy carbon (Sigradur®) and the platinum canula are connected to a direct current source and can be switched to serve either as the cathode or anode. For the recovery of the desired radionuclide, for example, (¹⁸F) fluoride from (¹⁸O) H₂O, the flow cell is filled with (¹⁸F) fluoride containing target water. The (¹⁸F) fluoride is anodically deposited on the surface of the cylinder and the (¹⁸O) water is transported out of the latter. The height of the zone at which the (¹⁸F) fluoride is anodically fixed is identical with the level of the (¹⁸O) water in the cell.

In order that the radioisotope fixed on the surface can be completely transferred to another liquid phase by reversal of the polarity of the electric field, it is necessary to match the amount of the educt supplied to the level in the cell to which the latter was filled with the (¹⁸O) water. For the subsequent (¹⁸F) fluoridation, therefore, a reaction volume must be provided which corresponds to that of the target water. Thus it is necessary to match the quantity of the educt so that it corresponds at the optimal educt concentration at this volume (for example 1.3 ml). Because of the very small quantities or proportions of these products (picomols to nanomols) with respect to the proportion of unoriented educt (μmol), difficulties in separation occur during purification and especially during chromatographic purification. Since the mass of the educt significantly exceeds the mass of the product, an HPL-chromatographic separation can only be run with poor resolution.

It is thus an object of the invention to provide a device and a method whereby the reaction volume can be reduced. It is a further object of the invention to reduce the amount of material of the educt by a multiple while maintaining the optimum educt concentration.

Starting from the preamble of claim 1, the objects are attained according to the invention with features given in the characterizing clause of claim 1. The objects are further achieved in accordance with the device of the characterizing part of claim 14.

With the flow cell according to the invention and the method, it is possible directly to reduce the cylinder volume (=reaction volume) and thereby reduce the quantity of the educt also by a multiple. The reduction of the quantity of the educt simplifies the chromatographic purification and enables a quantitative separation of the carrier-poor marker compound (product) from the educt. Since reduced educt quantities can be used, the costs are reduced and the economy of the method enhanced. Advantageous features are given in the dependent claims.

The drawing shows an embodiment of the method and the device according to the invention by way of example.

In the drawing:

FIG. 1 is a cross section through the flow cell in position I;

FIG. 2 is a cross section through the flow cell in position II; and

FIG. 3 is plan view through the flow cell in position II taken in the sectional plane.

FIG. 1 shows the flow cell 1 with a cylinder 2 receiving a canula 3 which is bounded from below a piston 4 with a bore 5 connected by a yoke 6 with a canula holder 7. The cylinder 2 can be filled with liquid or inert gas through the canula 3. The flow cell 1 is fixed by a mounting 8 and sealed. In the head part of the mounting 8, there are two feed lines 9 and 10 through which the gases can be fed to the device or carried away. In the head of the piston 11, there is a flat funnel 12 which opens in a bore 5. The cylinder 2 and the canula 3 are connected to a direct current source 13 and can be selectively switched for use as the cathode or anode. In position I, the canula 3 is located at the lower end of the cylinder 2. The piston 4 is located outside the cylinder 2. In the lower region 17 of the cylinder, two sealing rings 15 and 16 seal the piston 4 with respect to the cylinder 2.

In FIG. 2 the same features of the device have been represented by the same reference numerals. FIG. 2 shows the arrangement of the components of the flow cell 1 in Position II, the piston 4 has been shifted into the cylinder 2. The canula 3 is pushed out of the cylinder 2 by the amount to which the piston 4 projects into the cylinder 2. Between the piston 4 and the cylinder 2, an annular gap 14 is formed. In FIG. 2 at the lower portion of the cylinder, a section plane has been marked by the reference character “A”.

FIG. 3 shows a plan view of the flow cell 1 in position II in a section along the section plane A. The annular gap 14 can be seen between the piston 4 and the cylinder 2.

The invention is described by way of example below.

At the beginning of the reaction the components of the flow cell 1 are arranged, for example, as follows (see also FIG. 1; Position I); the lower opening of the canula 3, which is preferably made from platinum is located at the lower end 17 of the cylinder 2 and the piston 4, located externally of the cylinder 2. The flow cell 1 is filled through the bore 5 or the duct 3 with the (¹⁶F) fluoride containing target water, whereby the (¹⁸F) fluoride is anodically deposited on the surface of the cylinder 2 at which a DC voltage of, for example, 20 volts is applied via a DC voltage source 13. The canula 3 here serves as the cathode. The cylinder 2 is made in an advantageous embodiment of the device of a pore-free inert material, like for example glassy carbon (Sigradur®), a noble metal or platinum.

The piston 4 should preferably be made from an inert material. As suitable material, for example PEEK (polyetheretherketone), quartz glass or implement glass have been found to be suitable. It is, however, also possible to use a piston of an electrically conductive material which can then also be used as an electrode. The gap width or the difference in radius between the cylinder 2 and the piston 4 is dependent upon the fabrication method. Preferred is a radius difference between the cylinder 2 and the piston 4 of 0.4 mm. Suitable however also are gap widths of <0.2 mm. For the ratio of the radii between the cylinder (r₁) and the piston (r₂), the following equations can apply: F ₁ =r ₁ ²*π where F₁=the area of the cylinder 2 F ₂ =r ₂ ²*π where F₂=the area of the piston 4 F ₃ =F ₁ −F ₂=π((r ₁ ² −r ₂ ²) where F₃=the area of the gap 14 V ₃ =r ₁ ² −r ₂ ²=(r ₁ +r ₂)(r ₁ −r ₂) where V₃=the volume of the gap 14 V ₁ /V ₃ =r ₁ ² /r ₁ ² −r ₂ ² =r ₁ ²/(r ₁ +r ₂)(r ₁ −r ₂) where V₁=the volume of the cylinders 2.

After the filling of the flow cell with the target solution (for example ¹⁸O water), the radioisotope (for example ¹⁸F fluoride) is deposited on the inner surface of the cylinder 2 and the ¹⁸O water is transported out of the flow cell 1 through the bore 5 in the piston 4. The height of the zone in which the (¹⁸F) fluoride is anodically fixed, corresponds to the filling level of the ¹⁸O water in the cylinder 2. The (¹⁸F) fluoride fixed on the surface of the cylinder 2 is then completely dissolved in another liquid phase, like for example an organic phase transfer catalyst containing solution ((Kc2.2.2)₂C₂O₄ in dimethylsulfoxide=DMSO) by reversal of the electrical field. For that purpose it is necessary that the filling level of this liquid phase in the cylinder 2 match the filling state of the ¹⁸O water which was previously set. To avoid the need for a reaction volume corresponding in amount to the target water volume for the subsequent nucleophilic (¹⁸F) fluoridation, a displacement effect of the piston 4 is used. The piston 4 is shifted upwardly by a movement of the yoke 6 in this direction. Simultaneously the canula 3 is shifted in the cylinder 2 corresponding to the height of the piston 4 out of the cylinder 2. The volume that thus must be introduced into the cylinder 2 must correspond to the volume of the gap 14 that is formed when the piston 4 projects into the cell 1 (see FIG. 2, Position II) such that the upper end of the piston 4 coincides with the filling level which has been determined by the (¹⁸F) fluoride fixed on the surface of the cylinder 2. In an advantageous configuration of the device, the ratio of the volume (V₁) of the cylinder 2 to the volume (V₃) of the gap amounts to 4:1 to 10:1. In an especially preferred configuration of the device, it amounts to 4:1. With an ¹⁸O water volume of, for example 1.3 ml, the volume of the gap 14 at a filling level can amount to about 0.29 mm. When the piston is shifted upwardly sufficiently that the upper end of the piston 4 coincides with the filling level determined by the (¹⁸F) fluoride fixed on the surface of the cylinder (see FIG. 2, piston B), the (¹⁸F) fluoride can be transferred to the reaction solution by applying an electric belt (with the (Sigradur® as the cathode). In this position, only the gap volume 14 is filled. The solution is sealed at the lower end by two annular cylinders 15 and 16 (for example O-rings) with respect to the piston 4 so that a lateral outflow of liquid from the lower end of the cylinder is prevented.

For emptying the reaction vessel, the vessel 4 is again lowered and the liquid transported outwardly through the canula 3 or the bore 5 of the piston 4.

In an advantageous configuration of the device and the method, the feed or the evacuation of the (¹⁸F) fluoride-containing target water and the organic solvent are effected through different conduits. When, for example, the supply of the (¹⁸F) fluoride-containing target water is effected through the conduit 3, the transport of the organic solvent which is used for desorption of the product is effected through the bore 5 to avoid a contamination of the conduit 3. Thus a high effort cleaning of the conduit for the target water can be avoided. The transport of the target water will be self-understood to be possible also through the bore 5 and the transport of the organic solvent correspondingly through the conduit 3. It is important for a device which can be easily manipulated and the method that a separate conduit is provided for each of the different liquids.

Through the method of the invention and the device it is possible to reduce the edict quantity. This reduction in the mass of the educt is especially advantageous for the subsequent chromatographic separation of the carrier-poor ¹⁸F-labeled product from the educt. In previously known methods and with previously known devices for the separation of the carrier-free radionuclide and its radiochemical reaction, the educt quantity is significantly greater. Through the method and device according to the invention, the volume of the educt solution and thus the quantity of the educt is reduced by a multiple (at least 3 to 4 times) so that the chromatographic separation of educt and the ¹⁸F-labeled product is significantly improved.

The reduction of the absolute educt quantity thus gives rise to a cost saving and therewith an improvement in the economy of the method.

EXAMPLE ¹⁸F-Labeling of N-Methylbenperidol

The (¹⁸F) fluoride-containing ¹⁸O water (1.3 ml) coming from the target of the cyclotron is transported into the flow cell 1 through the bore 5 of the piston 4. Upon application of an electrical voltage of 20 volts from a direct current source 13 (anode=cylinder (2) of carbon glass), the carrier-poor radio isotope is identically adsorbed within about 8 minutes on the surface of the cylinder 2. The ¹⁸O water is driven out through the bore 5 by means of helium. To dry the cylinder wall, the flow cell is filled once or twice each with 1.6 ml of water-free dimethylsuloxide (DMSO) and emptied through the canula 3 serving as the counterelectrode. Through the canula 3, a solution of 5 mg Kryptate ([Kc2.2.2]₂CO₃ in 300 μl DMSO) is introduced into the flow cell 1 and piston 4 shifted by a motor so that the liquid surface reaches the upper boundary of the anodically deposited ¹⁸F fluoride. The potential is reversed (−2V) and the cylinder is heated for 5 minutes to 100° C. After depolarization of the flow cell, the piston is brought into its lower position and through the canula 3 of a solution of 2 mg of N-methyl-desfluor-nitro-benperidol in 150 μl of DMSO is supplied. The piston 4 is shifted again into the upper position and the flow cell is heated for 10 minutes to 150° C. Then the flow cell is cooled with compressed air to ambient temperature. The flow cell is emptied through the canula 3, is washed with about 0.8 ml acetonitrile at 50° C. and this solution is mixed with the DMSO product solution by a subsequent HPL-chromatography, the radiotracer (¹⁸F) N-methylbenperidol is purified and isolated. 

1. A flow cell (1) for separating carrier-free radionuclides from liquid or liquifiable target material and its radiochemical reaction, characterized by a gap (14) between cylinder (2) and the piston (4).
 2. The flow cell (1) according to claim 1, characterized in that the diameter of the piston (4) is smaller than the diameter of the cylinder (2).
 3. The flow cell (1) according to claim 1, characterized in that the volume ratio between cylinder (2) and gap (14) amounts to 4:1 to 10:1.
 4. The flow cell (1) according to claim 1, characterized in that the piston (4) is comprised of chemically inert material.
 5. The flow cell (1) according to claim 1, characterized in that the piston (4) is composed of PEEK, implement glass or quartz glass.
 6. The flow cell (1) according to claim 1, characterized in that the piston (4) has a bore (5).
 7. The flow cell (1) according to claim 1, characterized in that the piston (4) has a central bore (5).
 8. The flow cell (1) according to claim 1, characterized in that the cylinder (2) has a pore-free inert surface.
 9. The flow cell (1) according to one of claims 1 to 8 claim 1, characterized in that the cylinder (2) is composed of chemically inert material.
 10. The flow cell (1) according to claim 1, characterized in that the cylinder (2) is composed of carbon glass, a noble metal or platinum.
 11. The flow cell (1) according to claim 1, characterized in that the surface of the cylinder (2) is electrically charged.
 12. The flow cell (1) according to claim 1, characterized in that the canula (3) is electrically charged.
 13. The flow cell (1) according to claim 1, characterized in that the canula (3) is the counter electrode to the electrically-charged cylinder (2).
 14. A method of separating carrier-free radionuclides from liquid or liquifiable target material and its radiochemical reaction, characterized in that a flow cell according to claim 1 is used.
 15. The method according to claim 14, characterized in that after fixing of the radionuclide on the surface of the cylinder (2), the piston (4) is shifted into the cylinder and simultaneously the canula (3) is correspondingly shoved out of the cylinder.
 16. The method according to claim 14, characterized in that the upper end of the piston (4) is shoved up to the level of the target material in the cylinder (2).
 17. The method according to claim 14, characterized in that the volume of the gap (14) piston (4) and cylinder (2) as filled with a liquid phase.
 18. The method according to claim 14, characterized in that after desorption of the radionuclide into the liquid phase the piston (4) is shifted out of the cylinder (2). 